Louis F. Diehl

The National Cancer Data Base Report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia †

The natural history of chronic lymphocytic leukemia (CLL) is changing, although the reasons (potential changes in the diseases biology or in patterns in patient characteristics, treatment, or referral) are unclear.

Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia.

PURPOSE A report of the clinical features, treatment, and outcome of patients who developed hemolytic anemia (HA) temporally associated with fludarabine (Fludara; Berlex Laboratories, Richmond, CA) therapy for chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS Data on 24 patients who developed HA related to fludarabine therapy were collected from the Spontaneous Reporting System of the Food and Drug Administration (FDA) and the Walter Reed Army Medical Center (Washington, DC). RESULTS Seventeen (71%) patients developed HA after either the first, second, or third cycle of this drug. The longest duration of fludarabine therapy before HA occurred was six cycles. The median decline in hematocrit from baseline during the hemolytic episode was 14.1 (range, 8.0 to 28.9) for the 18 patients for whom this information was available. For the 11 patients for whom transfusion requirements were known, the number of transfusions administered ranged between three and 36. Seven (29%) patients died of medical complications associated with the HA. Seven of eight patients who were re-challenged with fludarabine after an episode of HA developed recurrent HA, and three of these patients died. CONCLUSION HA associated with fludarabine therapy appears to be uncommon, but it can be severe and fatal, especially if a patient is re-treated with this drug after a previous episode of HA. The mechanism of this toxicity is unknown, but it may be caused by the release of a suppressed auto-antibody to a native red cell antigen.

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5+ CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgVH mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

D-dimer assay predicts mortality in critically ill patients without disseminated intravascular coagulation or venous thromboembolic disease

Objective: To determine if D-dimer predicts outcomes in critically ill patients. Design: Observational, cohort study. Setting: Medical intensive care unit (MICU) of a tertiary care hospital. Patients and participants: Seventy-four patients consecutively admitted to the MICU. Interventions: D-dimer was measured by latex agglutination within 12 h of admission to the MICU. Measurements and results: Of the study population, 43.2 % had positive D-dimers. The in-hospital mortality rate in D-dimer positive patients was 28.1 % as compared to 7.1 % in D-dimer negative subjects (p = 0.024). D-dimer positive patients had significantly greater frequencies of venous thromboses (21.9 % vs 4.8 %, p = 0.035). Conclusions: The D-dimer assay identifies patients at increased risk for mortality and may be a more sensitive test to determine the presence of underlying microvascular pathology in critically ill patients. A positive D-dimer at admission to the MICU is associated with an increased risk for the later development of a venous thromboembolic event (VTE).

A comparison of randomized concurrent control groups with matched historical control groups: are historical controls valid?

The use of a historical control group is predicated on the assumption that survival and relapse-free survival in the historical control group closely approximate the survival and relapse-free survival in a randomized concurrent control group. This assumption has never been tested. This study compares survival and relapse-free survival in randomized control groups with historical control groups matched for disease, stage, and follow-up. Of the 43 matched control groups, 42% varied by more than 10 percentage points, 21% varied by more than 20 percentage points, and 5% varied by more than 30 percentage points. Of the 18 that varied by greater than 10 percentage points, 17 had superior survival or relapse-free survival in the randomized concurrent control group. This study indicates that the assumption that historical control groups may replace randomized concurrent control groups is not valid.

In Vivo Treatment Sensitivity Testing With Positron Emission Tomography/Computed Tomography After One Cycle of Chemotherapy for Hodgkin Lymphoma

PURPOSE Negative [(18)F]fluorodeoxyglucose (FDG) -positron emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy indicates a favorable prognosis in Hodgkin lymphoma (HL). We hypothesized that the negative predictive value would be even higher in patients responding rapidly enough to be PET negative after one cycle. This prospective study aimed to assess the prognostic value of PET after one cycle of chemotherapy in HL and to assess the dynamics of FDG uptake after one cycle (PET1) and after two cycles (PET2). PATIENTS AND METHODS All PET scans were read by two blinded, independent reviewers in different countries, according to the Deauville five-point scale. The main end point was progression-free survival (PFS) after 2 years. RESULTS A total of 126 patients were included, and all had PET1; 89 patients had both PET1 and PET2. The prognostic value of PET1 was statistically significant with respect to both PFS and overall survival. Two-year PFS for PET1-negative and PET1-positive patients was 94.1% and 40.8%, respectively. Among those with both PET1 and PET2, 2-year PFS was 98.3% and 38.5% for PET1-negative and PET1-positive patients and 90.2% and 23.1% for PET2-negative and PET2-positive patients, respectively. No PET1-negative patient was PET2 positive. CONCLUSION PET after one cycle of chemotherapy is highly prognostic in HL. No other prognostic tool identifies a group of patients with HL with a more favorable outcome than those patients with a negative PET1. In the absence of precise pretherapeutic predictive markers, PET1 is the best method for response-adapted strategies designed to select patients for less intensive treatment.

Impact of consolidation radiation therapy in stage III-IV diffuse large B-cell lymphoma with negative post-chemotherapy radiologic imaging.

PURPOSE While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. METHODS AND MATERIALS Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. RESULTS Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). CONCLUSIONS Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.

Systemic Interleukin-2 and Adoptive Transfer of Lymphokine-Activated Killer Cells Improves Antibody-Dependent Cellular Cytotoxicity in Patients with Relapsed B-Cell Lymphoma Treated with Rituximab

Purpose: Murine models have shown that antibody-dependent cellular cytotoxicity (ADCC) can be improved with addition of lymphokine-activated killer (LAK) cells to monoclonal antibodies. A pilot trial of rituximab and LAK cells in patients with rituximab-refractory CD20+ lymphoma was conducted to evaluate this approach. Experimental Design: Ten patients received 3 million units/m2 of interleukin-2 (IL-2) i.v. qd on days 1 to 5 and leukapheresed on days 8, 9, and 10. The leukapheresis product was cultured with IL-2 for 48 h to produce LAK cells. Patients then received 375 mg/m2 i.v. rituximab and LAK cells on days 10, 11, and 12. The patients also received 3 million units/m2 of IL-2 i.v. for 5 days starting day 10. For safety purposes, the first three patients did not receive any LAK cell infusions. Results: The LAK cell infusions improved the ADCC activity of peripheral blood lymphocytes compared with pretreatment activity and prevented the decline in ADCC seen after infusion of rituximab alone. Therapy was well tolerated and the most clinically significant toxicities were fever and fatigue. Two patients achieved a partial remission and five had stable disease. Conclusions: The results from these studies suggest that the addition of LAK cells to rituximab augments ADCC in patients with rituximab-refractory lymphoma.

Herpes virus infections occur frequently following treatment with fludarabine: results of a prospective natural history study.

We performed a prospective infectious natural history study of 21 patients with low‐grade lymphoproliferative disorders receiving fludarabine as initial (n = 5) or salvage (n = 16) therapy. 12 (57%) of these patients developed herpes zoster (n = 9), herpes simplex I (n = 1) or herpes simplex II (n = 2) infections at a median of 8 (range 1–17) months following initiation of fludarabine, with 75% of these having completed therapy. All patients with herpes zoster developed severe post‐herpetic neuralgia. Factors differentiating patients developing these infections included older age and low serum IgG or IgA. Based upon these prospective data, we conclude that herpes virus infections frequently occur following fludarabine treatment, necessitating aggressive patient education and new prophylactic strategies.